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Abstract Background Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB. Methods We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching. Results We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs. Conclusion Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Background: Antiretroviral therapy in human immunodeficiency virus (HIV)-infected women and blacks merits particular scrutiny because these groups have been underrepresented in clinical trials., Methods: To document the effects of raltegravir across sex and racial lines, we conducted a pooled subgroup analysis of the efficacy and safety of raltegravir 400 mg BID plus tenofovir-emtricitabine by sex (women vs men) and self-identified race (black vs non-black) using phase 3 studies in treatment-naive patients., Results: Study participants included 42 black women, 102 non-black women, 48 black men, and 477 non-black men. Clade B infections were less common in women (43.8%) than men (84.6%) and in blacks (45.6%) than non-blacks (80.5%). Baseline CD4 counts were ≤200 cells/µL in 52.2% of blacks and 31.6% of non-blacks. Black men had the largest proportion of patients with baseline CD4 counts <50 cells/µL and the highest nontreatment-related discontinuation rate among the 4 sex-by-race subgroups. Human immunodeficiency virus-ribonucleic acid levels <50 copies/mL were achieved at week 48 in 92.7% (95% confidence interval [CI], 80.1-98.5) of black women, 93.6% (95% CI, 86.6-97.6) of non-black women, 82.9% (95% CI, 67.9-92.8) of black men, and 91.4% (95% CI, 88.4-93.8) of non-black men. Serious clinical adverse events were reported in 9.0% of women versus 8.8% of men and in 11.1% of blacks versus 8.5% of non-blacks., Conclusions: In this post hoc analysis of patients with previously untreated HIV-1 infection receiving raltegravir plus tenofovir-emtricitabine, generally comparable results were achieved across sex and racial subgroups. However, black men had a lower response rate than either black women or non-black men, partially attributable to lower baseline CD4 counts and higher discontinuation rates., (© The Author 2017. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

To differentiate between the effects that antiretroviral drugs have on the endothelium and the secondary effects that they have on immune function, viral load, and dyslipidemia, 6 non-human immunodeficiency virus-infected human subjects were treated with lopinavir-ritonavir for 1 month and, on the basis of forearm blood flow, the treatment's effects on endothelial cell function were measured. Surprisingly, after exposure to lopinavir-ritonavir, absolute forearm blood-flow responses to the endothelium-dependent vasodilator, acetylcholine, increased significantly (P=.03), and forearm blood flow decreased to a greater extent during specific inhibition of NO synthase by N(G)-monomethyl-L-arginine. Thus, in this small cohort of subjects, short-term treatment with lopinavir-ritonavir does not appear to directly promote endothelial cell dysfunction.

Potent antiretroviral therapy stimulates robust and durable immune reconstitution among profoundly immunosuppressed patients that is clinically important. Fifteen patients with cytomegalovirus retinitis (CMVR) were followed after discontinuing anti-cytomegalovirus therapy. No patients had progression or relapse for a median of 51 months. Survival from the diagnosis of CMVR was universal for up to 95 months, with an observation period averaging more than 6 years. The CD4 cell count continued to rise through the fourth year of follow-up.

We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4(+) or CD8(+) T cell counts or the percentage of cells that were CD4(+)CD25(+), CD8(+)CD25(+), or CD4(+)DR(+), patients who received SIT had a significantly higher percentage of CD8(+)CD38(+) and CD8(+)DR(+) cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cycle SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters.

Objective: To examine the prevalence and clinical correlates of subsequently measurable viremia in HIV-infected patients who have achieved viral suppression below the limits of quantification (< 50 copies/ml)., Design: Non-randomized dynamic cohort study of ambulatory HIV patients in nine HIV clinics in eight cities., Patients: Patients had two consecutive HIV-1 RNA levels < 50 copies/ml (minimum, 2 months apart) that were followed by at least two more viral level determinations while remaining on the same antiretroviral therapy (ART) between January 1997 and June 2000 (median 485 days). Transiently viremic patients were defined having a subsequently measurable viremia but again achieved suppression < 50 copies/ml., Results: Of the 448 patients, 122 (27.2%) had transient viremia, 19 (4.2%) had lasting low-level viremia and 33 (7.4%) had lasting high-level viremia (defined as 50-400 and > 400 copies/ml, respectively). Only 16 (13.1%) of those who had transient viremia later had persistent viremia > 50 copies/ml. The occurrence of transient viremia did not vary with whether the patient was ART-naive or experienced (P = 0.31), or currently taking protease inhibitors or not (P = 0.08). On consistent ART, the median percentage increase in CD4 cell count was statistically different between subgroups of our cohort (Kruskal-Wallis, P = 0.002)., Conclusions: Transiently detectable viremia, usually 50-400 copies/ml, was frequent among patients who had two consecutive HIV-1 RNA levels below the limits of quantification. In this analysis, such viremia did not appear to affect the risk of developing lasting viremia. Caution is warranted before considering a regimen as 'failing' and changing medications., (Copyright 2002 Lippincott Williams & Wilkins)

Objective: To survey the evolution over the past decade of attitudes and practices of obstetricians in maternal-fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV)-infected pregnant women., Methods: Directors of all 65 approved maternal-fetal medicine training programs were sent questionnaires, responses to which were to reflect the consensus among members of their faculties. Programs were stratified based upon the number of HIV-infected pregnant patients cared for in the previous year., Results: Responses reflect experience with over 1000 infected pregnant women per year, nearly one-quarter with advanced disease. Combination antiretroviral therapy was prescribed by all respondents, universally in the 2nd and 3rd trimesters. A three-drug regimen (often containing a protease inhibitor) was used more often by those who treated at least 20 HIV-infected pregnant patients per year than by those programs seeing a lower number of patients (80 vs 59%). Despite the known and unknown risks of the use of antiretrovirals during pregnancy, only half of all responding programs report adverse events to the Antiretroviral Pregnancy Registry; reporting was more common among the institutions seeing a higher number of patients (61 vs 45%). Seventy-eight percent of higher volume programs enroll their patients in clinical studies, usually multicenter, versus 35% of lower volume programs., Conclusions: Care for HIV+ pregnant women has dramatically changed over the past decade. Antiretroviral therapy is now universally prescribed by physicians involved in maternal-fetal medicine training programs. Given limited experience with these agents in the setting of pregnancy, it is essential for maternal-fetal medicine practitioners to actively report on adverse events and participate in clinical trials.